Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 53, Issue 3, Pages 1159-1171Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm9014636
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Funding
- CNRS
- INSERM
- ULP
- European Commission [LSHG-CT-2006-031220]
- Spanish MEC [SAF2004-01885, SAF2007-67205]
- Xunta de Galicia [INCITE08P-XIB-209130PR, ACEUIC-2006/XA050]
- Regional Council of Alsace
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The vitamin D nuclear receptor is a ligand-dependent transcription factor that controls multiple biological responses such as cell proliferation, immune responses, and bone mineralization. Numerous 1 alpha,25(OH)(2)D-3 analogues, which exhibit low calcemic side effects and/or antitumoral properties, have been synthesized. We recently showed that the synthetic analogue (20S,23S)-epoxymethano-1 alpha,25-dihydroxyvitamin D-3 (2a) acts as a 1 alpha,25(OH)(2)D-3 superagonist and exhibits both antiproliferative and prodifferentiating properties in vitro. Using this information and on the basis of the crystal structures of human VDR ligand binding domain (hVDR LBD) bound to 1 alpha,25(OH)(2)D-3,2 alpha-methyl-1 alpha,25(OH)(2)D-3, or 2a, we designed a novel analogue, 2 alpha-methyl-(20S,23S)-epoxymethano-1 alpha,25-dihydroxyvitamin D-3 (4a), in order to increase its transactivation potency. Here, we solved the crystal structures of the hVDR LBD in complex with the 4a (C23S) and its epimer 4b (C23R) and determined their correlation with specific biological outcomes.
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